Novel Pharmacological Inhibitors for Bacterial Protein Toxins

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (1 October 2016) | Viewed by 52632

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Institut für Pharmakologie und Toxikologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany
Interests: actin; bacterial protein toxins; macrophages; rho-gtpases; cellular uptake and intracellular membrane transport of bacterial toxins; interaction of bacterial toxins with host cell chaperones; bacterial toxins as molecular trojan horses for drug delivery
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Special Issue Information

Dear Colleagues,

Many medically relevant bacteria cause severe human and animal diseases because they produce and release protein toxins that target mammalian cells. Because the toxin-induced cell damage is the reason for the clinical symptoms, the targeted pharmacological inhibition of the cytotoxic mode of action of bacterial toxins should prevent or cure the respective toxin-associated disease. Toxin inhibitors might be beneficial when the toxin acts in the absence of the producing bacteria (e.g. food poisoning), but also in combination with antibiotics in infectious diseases when the toxin-producing bacteria are present. The focus of this Special Issue of Toxins is on development and characterization of novel inhibitors against bacterial toxins, e.g., toxin neutralizing antibodies, peptides or small compounds, as well as toxin pore blockers, which interfere with bacterial toxins and thereby protect cells from intoxication.

Prof. Dr. Holger Barth
Guest Editor

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Keywords

  • Antitoxin
  • bacterial toxin
  • cellular uptake
  • food poisoning
  • infectious disease
  • pore blocker

Published Papers (8 papers)

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Editorial

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173 KiB  
Editorial
An Introduction to the Toxins Special Issue on “Novel Pharmacological Inhibitors for Bacterial Protein Toxins”
by Holger Barth
Toxins 2017, 9(5), 160; https://doi.org/10.3390/toxins9050160 - 11 May 2017
Cited by 2 | Viewed by 3409
Abstract
Bacterial AB-type protein toxins that consist of an enzymatically active subunit (A) and a binding/transport subunit (B), are among the most toxic substances and represent the causative agents for a variety of severe human and animal diseases, such as in the context of [...] Read more.
Bacterial AB-type protein toxins that consist of an enzymatically active subunit (A) and a binding/transport subunit (B), are among the most toxic substances and represent the causative agents for a variety of severe human and animal diseases, such as in the context of infections, post-traumatic complications or food poisoning.[...] Full article
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)

Research

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3776 KiB  
Article
Role of p38alpha/beta MAP Kinase in Cell Susceptibility to Clostridium sordellii Lethal Toxin and Clostridium difficile Toxin B
by Ilona Schelle, Janina Bruening, Mareike Buetepage and Harald Genth
Toxins 2017, 9(1), 2; https://doi.org/10.3390/toxins9010002 - 22 Dec 2016
Cited by 3 | Viewed by 5073
Abstract
Lethal Toxin from Clostridium sordellii (TcsL), which is casually involved in the toxic shock syndrome and in gas gangrene, enters its target cells by receptor-mediated endocytosis. Inside the cell, TcsL mono-O-glucosylates and thereby inactivates Rac/Cdc42 and Ras subtype GTPases, resulting in actin reorganization [...] Read more.
Lethal Toxin from Clostridium sordellii (TcsL), which is casually involved in the toxic shock syndrome and in gas gangrene, enters its target cells by receptor-mediated endocytosis. Inside the cell, TcsL mono-O-glucosylates and thereby inactivates Rac/Cdc42 and Ras subtype GTPases, resulting in actin reorganization and an activation of p38 MAP kinase. While a role of p38 MAP kinase in TcsL-induced cell death is well established, data on a role of p38 MAP kinase in TcsL-induced actin reorganization are not available. In this study, TcsL-induced Rac/Cdc42 glucosylation and actin reorganization are differentially analyzed in p38alpha−/− MSCV empty vector MEFs and the corresponding cell line with reconstituted p38alpha expression (p38alpha−/− MSCV p38alpha MEFs). Genetic deletion of p38alpha results in reduced susceptibility of cells to TcsL-induced Rac/Cdc42 glucosylation and actin reorganization. Furthermore, SB203580, a pyridinyl imidazole inhibitor of p38alpha/beta MAP kinase, also protects cells from TcsL-induced effects in both p38−/− MSCV empty vector MEFs and in p38alpha−/− MSCV p38alpha MEFs, suggesting that inhibition of p38beta contributes to the protective effect of SB203580. In contrast, the effects of the related C. difficile Toxin B are responsive neither to SB203580 treatment nor to p38alpha deletion. In conclusion, the protective effects of SB203580 and of p38alpha deletion are likely not based on inhibition of the toxins’ glucosyltransferase activity rather than on inhibited endocytic uptake of specifically TcsL into target cells. Full article
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)
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3555 KiB  
Article
Probiotic Microorganisms Inhibit Epithelial Cell Internalization of Botulinum Neurotoxin Serotype A
by Tina I. Lam, Christina C. Tam, Larry H. Stanker and Luisa W. Cheng
Toxins 2016, 8(12), 377; https://doi.org/10.3390/toxins8120377 - 16 Dec 2016
Cited by 11 | Viewed by 6168
Abstract
Botulinum neurotoxins (BoNTs) are some of the most poisonous natural toxins known to man and are threats to public health and safety. Previous work from our laboratory showed that both BoNT serotype A complex and holotoxin can bind and transit through the intestinal [...] Read more.
Botulinum neurotoxins (BoNTs) are some of the most poisonous natural toxins known to man and are threats to public health and safety. Previous work from our laboratory showed that both BoNT serotype A complex and holotoxin can bind and transit through the intestinal epithelia to disseminate in the blood. The timing of BoNT/A toxin internalization was shown to be comparable in both the Caco-2 in vitro cell culture and in the oral mouse intoxication models. Probiotic microorganisms have been extensively studied for their beneficial effects in not only maintaining the normal gut mucosa but also protection from allergens, pathogens, and toxins. In this study, we evaluate whether probiotic microorganisms will block BoNT/A uptake in the in vitro cell culture system using Caco-2 cells. Several probiotics tested (Saccharomyces boulardii, Lactobacillus acidophilus, Lactobacillus rhamnosus LGG, and Lactobacillus reuteri) blocked BoNT/A uptake in a dose-dependent manner whereas a non-probiotic strain of Escherichia coli did not. We also showed that inhibition of BoNT/A uptake was not due to the degradation of BoNT/A nor by sequestration of toxin via binding to probiotics. These results show for the first time that probiotic treatment can inhibit BoNT/A binding and internalization in vitro and may lead to the development of new therapies. Full article
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)
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3167 KiB  
Article
Impact of Dendrimer Terminal Group Chemistry on Blockage of the Anthrax Toxin Channel: A Single Molecule Study
by Goli Yamini, Nnanya Kalu and Ekaterina M. Nestorovich
Toxins 2016, 8(11), 337; https://doi.org/10.3390/toxins8110337 - 15 Nov 2016
Cited by 6 | Viewed by 5967
Abstract
Nearly all the cationic molecules tested so far have been shown to reversibly block K+ current through the cation-selective PA63 channels of anthrax toxin in a wide nM–mM range of effective concentrations. A significant increase in channel-blocking activity of the cationic [...] Read more.
Nearly all the cationic molecules tested so far have been shown to reversibly block K+ current through the cation-selective PA63 channels of anthrax toxin in a wide nM–mM range of effective concentrations. A significant increase in channel-blocking activity of the cationic compounds was achieved when multiple copies of positively charged ligands were covalently linked to multivalent scaffolds, such as cyclodextrins and dendrimers. Even though multivalent binding can be strong when the individual bonds are relatively weak, for drug discovery purposes we often strive to design multivalent compounds with high individual functional group affinity toward the respective binding site on a multivalent target. Keeping this requirement in mind, here we perform a single-channel/single-molecule study to investigate kinetic parameters of anthrax toxin PA63 channel blockage by second-generation (G2) poly(amido amine) (PAMAM) dendrimers functionalized with different surface ligands, including G2-NH2, G2-OH, G2-succinamate, and G2-COONa. We found that the previously reported difference in IC50 values of the G2-OH/PA63 and G2-NH2/PA63 binding was determined by both on- and off-rates of the reversible dendrimer/channel binding reaction. In 1 M KCl, we observed a decrease of about three folds in k o n and a decrease of only about ten times in t r e s with G2-OH compared to G2-NH2. At the same time for both blockers, k o n and t r e s increased dramatically with transmembrane voltage increase. PAMAM dendrimers functionalized with negatively charged succinamate, but not carboxyl surface groups, still had some residual activity in inhibiting the anthrax toxin channels. At 100 mV, the on-rate of the G2-succinamate binding was comparable with that of G2-OH but showed weaker voltage dependence when compared to G2-OH and G2-NH2. The residence time of G2-succinamate in the channel exhibited opposite voltage dependence compared to G2-OH and G2-NH2, increasing with the cis-negative voltage increase. We also describe kinetics of the PA63 ion current modulation by two different types of the “imperfect” PAMAM dendrimers, the mixed-surface G2 75% OH 25% NH2 dendrimer and G3-NH2 dendron. At low voltages, both “imperfect” dendrimers show similar rate constants but significantly weaker voltage sensitivity when compared with the intact G2-NH2 PAMAM dendrimer. Full article
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)
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1435 KiB  
Article
Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells
by Angelika Kronhardt, Christoph Beitzinger, Holger Barth and Roland Benz
Toxins 2016, 8(8), 237; https://doi.org/10.3390/toxins8080237 - 10 Aug 2016
Cited by 10 | Viewed by 4424
Abstract
C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the [...] Read more.
C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells’ receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa. Full article
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)
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2143 KiB  
Article
Semicarbazone EGA Inhibits Uptake of Diphtheria Toxin into Human Cells and Protects Cells from Intoxication
by Leonie Schnell, Ann-Katrin Mittler, Andrea Mattarei, Domenico Azarnia Tehran, Cesare Montecucco and Holger Barth
Toxins 2016, 8(7), 221; https://doi.org/10.3390/toxins8070221 - 15 Jul 2016
Cited by 10 | Viewed by 5678
Abstract
Diphtheria toxin is a single-chain protein toxin that invades human cells by receptor-mediated endocytosis. In acidic endosomes, its translocation domain inserts into endosomal membranes and facilitates the transport of the catalytic domain (DTA) from endosomal lumen into the host cell cytosol. Here, DTA [...] Read more.
Diphtheria toxin is a single-chain protein toxin that invades human cells by receptor-mediated endocytosis. In acidic endosomes, its translocation domain inserts into endosomal membranes and facilitates the transport of the catalytic domain (DTA) from endosomal lumen into the host cell cytosol. Here, DTA ADP-ribosylates elongation factor 2 inhibits protein synthesis and leads to cell death. The compound 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA) has been previously shown to protect cells from various bacterial protein toxins which deliver their enzymatic subunits from acidic endosomes to the cytosol, including Bacillus anthracis lethal toxin and the binary clostridial actin ADP-ribosylating toxins C2, iota and Clostridium difficile binary toxin (CDT). Here, we demonstrate that EGA also protects human cells from diphtheria toxin by inhibiting the pH-dependent translocation of DTA across cell membranes. The results suggest that EGA might serve for treatment and/or prevention of the severe disease diphtheria. Full article
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)
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Review

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1884 KiB  
Review
Protection against Shiga Toxins
by Simona Kavaliauskiene, Anne Berit Dyve Lingelem, Tore Skotland and Kirsten Sandvig
Toxins 2017, 9(2), 44; https://doi.org/10.3390/toxins9020044 - 3 Feb 2017
Cited by 46 | Viewed by 9511
Abstract
Shiga toxins consist of an A-moiety and five B-moieties able to bind the neutral glycosphingolipid globotriaosylceramide (Gb3) on the cell surface. To intoxicate cells efficiently, the toxin A-moiety has to be cleaved by furin and transported retrogradely to the Golgi apparatus and to [...] Read more.
Shiga toxins consist of an A-moiety and five B-moieties able to bind the neutral glycosphingolipid globotriaosylceramide (Gb3) on the cell surface. To intoxicate cells efficiently, the toxin A-moiety has to be cleaved by furin and transported retrogradely to the Golgi apparatus and to the endoplasmic reticulum. The enzymatically active part of the A-moiety is then translocated to the cytosol, where it inhibits protein synthesis and in some cell types induces apoptosis. Protection of cells can be provided either by inhibiting binding of the toxin to cells or by interfering with any of the subsequent steps required for its toxic effect. In this article we provide a brief overview of the interaction of Shiga toxins with cells, describe some compounds and conditions found to protect cells against Shiga toxins, and discuss whether they might also provide protection in animals and humans. Full article
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)
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1671 KiB  
Review
Clostridium perfringens Sialidases: Potential Contributors to Intestinal Pathogenesis and Therapeutic Targets
by Jihong Li, Francisco A. Uzal and Bruce A. McClane
Toxins 2016, 8(11), 341; https://doi.org/10.3390/toxins8110341 - 19 Nov 2016
Cited by 43 | Viewed by 11672
Abstract
Clostridium perfringens is a major cause of histotoxic and intestinal infections of humans and other animals. This Gram-positive anaerobic bacterium can produce up to three sialidases named NanH, NanI, and NanJ. The role of sialidases in histotoxic infections, such as gas gangrene (clostridial [...] Read more.
Clostridium perfringens is a major cause of histotoxic and intestinal infections of humans and other animals. This Gram-positive anaerobic bacterium can produce up to three sialidases named NanH, NanI, and NanJ. The role of sialidases in histotoxic infections, such as gas gangrene (clostridial myonecrosis), remains equivocal. However, recent in vitro studies suggest that NanI may contribute to intestinal virulence by upregulating production of some toxins associated with intestinal infection, increasing the binding and activity of some of those toxins, and enhancing adherence of C. perfringens to intestinal cells. Possible contributions of NanI to intestinal colonization are further supported by observations that the C. perfringens strains causing acute food poisoning in humans often lack the nanI gene, while other C. perfringens strains causing chronic intestinal infections in humans usually carry a nanI gene. Certain sialidase inhibitors have been shown to block NanI activity and reduce C. perfringens adherence to cultured enterocyte-like cells, opening the possibility that sialidase inhibitors could be useful therapeutics against C. perfringens intestinal infections. These initial in vitro observations should be tested for their in vivo significance using animal models of intestinal infections. Full article
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)
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